Short and Long-Term Cardiovascular Sequelae after SARS-CoV-2 Infection: A Narrative Review Focusing on Athletes

Cardiovascular (CV) involvement after severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection was found to be frequent among the general population, especially in the pre-vaccination era, and particularly for hospitalized patients or those who experienced a more severe course of the disease. The spectrum of CV disease varies; however, acute myocarditis is particularly fearsome for the athletic population due to the possible associated risk of malignant arrhythmias during training. Alarming percentages of CV injuries, even in young and healthy athletes with a benign course of the disease, arose from a few initial studies limited to case series. Subsequent single-center studies and larger observational registries reported a lower prevalence of SARS-CoV2 CV involvement in athletes. Studies showing the occurrence of CV adverse events during follow-up periods are now available. The objective of our narrative review is to provide an updated summary of the literature on CV involvement after coronavirus disease 2019, both in the early post-infection period and over a longer period of time, with a focus on athletic populations.


Introduction
It has been nearly three years since the World Health Organization declared the coronavirus disease 2019 (COVID-19) pandemic outbreak in March 2020, caused by the diffusion of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2). The pandemic caused millions of deaths, and concerns about COVID-19 sequelae have been raised. Cardiovascular (CV) involvement is frequent in patients suffering from COVID-19, with various manifestations ranging from asymptomatic myo-pericarditis to arrhythmias, pulmonary emboli, myocardial infarction, and cardiogenic shock [1][2][3][4]. The COVID-19 pandemic has had a variety of consequences, even in the world of sports. Firstly, at the beginning of the pandemic, sports competitions at the national and international level, including the 2020 Olympic games, were withdrawn or postponed. Secondly, the possible CV involvement of COVID-19 could have a cascade effect on sport participation. The CV involvement during an infection and possibly related sequelae generated concerns not only in the general population but also in the athletic one, particularly during the pre-vaccination era. Over the past three years, a wide number of studies have been published on the short-term CV sequelae in athletes, while less is known regarding possible long-term effects on the CV system. This narrative review focuses on CV sequelae in athletes. The overall aim of the review is

COVID-19 and Cardiovascular Involvement in Athletes
The first evidence of CV involvement in athletes was described during the first wave of the pandemic and initially came from case series. One of the first reports showed an alarming prevalence of 15% of myocarditis, detected by cardiac magnetic resonance (CMR), in a cohort of 26 athletes who were asymptomatic and without other abnormalities [16]. Brito et al. also described 39% pericardial involvement, with 12.5% and 16.7% concomitant and isolated myocardial involvement, respectively, at CMR and transthoracic echocardiography (TTE) in a cohort of 54 collegiate athletes [17]. These initial two case series reported the highest percentages of athletes' COVID-19 myocardial and pericardial involvement, which were not confirmed by the following studies. On the contrary, other reports on small cohorts did not find evidence of definite cardiovascular involvement after COVID-19 [18][19][20][21][22][23][24].
All the studies reported so far have applied a similar protocol based on ECG, roponin, and TTE. Results from studies applying different RTP protocols included exercise testing or cardiopulmonary exercise testing (CPET). Maestrini et al. screened a cohort of 47 Olympic athletes with previous SARS-CoV-2 disease based on the RTP protocol recommended during the first phase of the pandemic (including a blood test, ECG, TTE, CPET, and 24-h Holter ECG monitoring). CMR was also included in this study. Acute myocarditis was detected in 2% of the athletes, and those athletes presented with symptoms, new exercise-induced premature ventricular contractions (PVCs), and increased troponin T [28]. In a subsequent study on 219 athletes, at the RTP evaluation, 9.5% of athletes presented with uncommon PVCs at CPET or Holter monitoring, but the prevalence of myocarditis was 0.9% [29]. Interestingly, all athletes had good performances after recovering from the infection without functional limitations.
Cavigli et al. found 3.3% of cardiac abnormalities in a cohort of 90 professional and non-professional athletes from a single-center study recovering from COVID-19 (one myo-pericarditis and two pericarditis) [30].
Regardless of the protocol applied, all the mentioned studies suffer from several limitations. First, they are single-center, often retrospective, with different interval times between infection and CV evaluation and different methodologies and protocols applied. Later, multicenter registries collected data on a larger scale to confirm the low prevalence of cardiovascular consequences (Table 1). Moulson et al. performed an analysis on 3018 collegiate athletes from the outcome registry for cardiac conditions in athletes (ORCCA) based on ECG, troponin, and TTE (the so-called "triad test"). The diagnosis of myocarditis was divided into definite, probable, and possible categories based on imaging and biomarker criteria, and the overall prevalence was 0.7% of the entire population. In addition, the authors explored the diagnostic role of CMR screening athletes using two different protocols: in one group, CMR was requested based on clinical indication, while in the other, it was performed as a screening tool on all athletes. The authors found that the diagnostic power of CMR for SARS-CoV-2 cardiac involvement was 4.2 times higher for a clinically indicated CMR [12.6% (15/119) vs. 3.0% (6/198)]. Importantly, at multivariate analysis, cardiopulmonary symptoms and abnormal triad tests were predictive of cardiac involvement [32]. Daniels et al. analyzed data on 1597 athletes from 13 universities participating in the Big Ten COVID-19 Cardiac Registry who were recovering from SARS-CoV2 infection and undergoing CV evaluation, which includes a CMR. They showed a prevalence of myocarditis of 2.3% [33]. In contrast to Moulson et al., this study also showed that performing CMR imaging as a screening strategy provided an increased prevalence of cardiac involvement of 7.4-fold and 2.8-fold over a symptoms-driven strategy and the triad test strategy, respectively. However, the clinical significance of isolated positive CMR findings is questionable. Subsequent multicenter studies confirmed a low percentage of cardiac abnormalities at CV evaluation before RTP, finding a prevalence of myocarditis that ranges from 0% to 1.4% [34][35][36][37].    CPET follow-up (13 athletes): 69% reduction in symptoms, improvement in peak vO2 and oxygen pulse, and reduction in resting and peak heart rate.     − Definite or probable SARS-CoV-2 myocardial or myo-pericardial involvement: 0.6% − They were restricted from the sport and were successfully returned to the sport after a median of 86 days (IQR 33-90) − Follow-up cardiac imaging: 71% athletes − Follow-up CMR: 70% complete resolution, 10% partial resolution, and 20% persistent CMR abnormalities − Clinical follow-up: 0.05% (2 cases) adverse cardiovascular events, both in athletes without SARS-CoV-2 cardiac involvement Finally, in a multi-center study focused on 571 junior athletes, the RTP evaluation, including a 12-lead resting ECG, exercise testing, and echocardiography, showed cardiac complications were uncommon and not associated with malignant ventricular arrhythmias [41].

COVID-19 and Cardiovascular Involvement in Athletes: RTP Protocols
With the increasing evidence of possible SARS-CoV-2-related sequelae, different scientific societies have proposed screening protocols for the return to play (RTP) of athletes recovering from the infection, based primarily on expert opinion [42][43][44][45]. The approaches proposed were different and based on different diagnostic algorithms, and they evolved in parallel with advances in pathophysiology understanding and accumulating evidence. Thus, these consensus documents were progressively updated. The American College of Cardiology (ACC) has recently published an updated consensus on the decision pathway for CV sequelae in adults after recovery from COVID-19, including a section dedicated to athletic groups [46]. Previous documents recommended a common approach based on ECG, troponin, and TTE as a screening protocol, the so-called "triad testing" [44,45]. Currently, this approach is reserved only for hospitalized athletes or those who experienced cardio-pulmonary symptoms during the infection, developed new-onset cardio-pulmonary symptoms during the return to physical activity, or had post-acute SARS-CoV2 sequelae [46]. Recently, a European consensus on the RTP in children and junior athletes has been published, recommending a strategy based on the disease severity and the presence of cardiac symptoms to screen athletes who need further CV evaluation after COVID-19 [47]. Athletes who experienced a more severe course of the infection or manifested cardiac symptoms should undergo resting ECG, blood testing, TTE, exercise testing, 24 h Holter ECG monitoring, and CMR if clinically indicated. Individuals with asymptomatic or mild symptoms should be evaluated with an accurate anamnesis and physical examination, and they should be informed about the possibility of CV symptoms occurring during the return to physical activity [47].

Short-and Long-Term Follow-up
The vast majority of the studies were focused on the athletes' evaluation at the RTP assessment following SARS-CoV-2 infection, with no data on longer follow-up in those athletes with CV involvement. In a few single-center studies, data on longer follow-up in those athletes with myocardial involvement is available, but it is limited to sporadic cases. In such cases, no adverse events after resuming exercise or during competitions were reported [18,24]. The recovery was reported as complete or partially complete, with LGE or arrhythmias persisting (Table 1) [25,[28][29][30].
All the registries and multi-center studies on larger cohorts reported results based on clinical follow-up (Table 1). Moulson et al. demonstrated the absence of adverse cardiac events in athletes with definite or probable SARS-CoV2 involvement that were observed for a median of 130 days. Regarding the cohort of positive athletes (median follow-up: 113 days), there was only one (0.3%) resuscitated cardiac arrest, which was probably unrelated to a previous SARS-CoV2 infection since the CMR acquired early after COVID-19 symptoms was negative [32]. Similarly, Chevalier et al. reported over a follow-up period of 289 ± 56 days, with only one case of ventricular tachycardia in an athlete recovered from COVID-19. However, the individual underwent a comprehensive CV evaluation post-infection without any abnormal CV findings [35]. Daniels et al. performed a CMR follow-up in athletes with myocarditis after 9.4 ± 3.1 weeks, finding a complete resolution of abnormalities in 40.7% of the subgroup, while the other 59.3% showed the resolution of oedema with the persistence of LGE [33]. Other registries did not report cardiac adverse events among athletes who underwent cardiac screening and returned to sports competitions [34,37]. Petek et al. conducted a prospective observational study on 3644 athletes from the ORCCA registry focused on persistent or exertional symptoms upon return to exercise after SARS-CoV-2 infection, finding a low prevalence of persistent symptoms (0.12% and 0.06% of athletes complaining of symptoms lasting more than 3 weeks and 12 weeks, respectively). Exertional cardio-pulmonary symptoms were present in 4% of the athletes, the most frequent being shortness of breath and chest pain, and SARS-CoV2 sequelae were diagnosed in 8.8% of athletes with exertional symptoms. Definite or probable SARS-CoV2-related cardiac involvement was diagnosed in 20.8% (5/24) of athletes with exercise-induced chest pain who underwent CMR (three definite pericardial, one definite myo-pericardial, and one probable myo-pericardial), while none of the athletes with other exertional symptoms were diagnosed with cardiac involvement. The authors concluded that SARS-CoV2 cardiac involvement is rare among young competitive athletes and that CV evaluation before RTP has to follow a symptom-based strategy, especially considering chest pain during exercise as a red flag for COVID-19 cardiac consequences [39]. Similarly, Moulson et al. conducted a study on a small cohort of 21 athletes who had persistent or new onset cardio-pulmonary symptoms after COVID-19 and were undergoing a comprehensive CV evaluation with CMR based on clinical indication. No evidence of active inflammatory heart disease was found. Moreover, the athletes performed CPET, showing similar values of peak oxygen consumption (vO 2 ) but a lower breathing reserve and, more frequently, abnormal spirometry when compared with a group of COVID-19-negative athletic controls. Thirteen COVID-19-positive athletes underwent CPET at follow-up (4.8 ± 1.9 months), with a resolution or reduction in cardiopulmonary symptoms in 69% of them and a concomitant lower peak heart rate and higher values of peak oxygen consumption [38].
Finally, a more recent study by Petek et al. on 3675 athletes with previous COVID-19 focusing on cardiovascular outcomes at a median follow-up of 1.12 years found 0.6% of definite or probable cardiac involvement (myocardial or myo-pericardial) after the infection and only two adverse cardiac events (0.05%) in the group of COVID-19-positive athletes without SARS-CoV2 CV involvement. One athlete experienced a resuscitated cardiac arrest that was not linked to the previous infection that occurred more than three months earlier.
The other athlete had a new onset of atrial fibrillation, possibly related to SARS-CoV2 disease because it occurred less than two weeks before the episode [40].

Limitations and Quality of the Involved Studies
Apart from a few earlier studies, the current literature demonstrates the low prevalence of CV involvement in athletes after COVID-19. However, the studies involved in this narrative review show some limitations. First, most of them are single-center studies with small populations of athletes [16][17][18][19][20][21]23,27,28,38]. Moreover, some works have been conducted retrospectively [20,[22][23][24][25]27,31]. There are no randomized controlled trials available. Finally, most works include professional and non-professional athletes with heterogeneous training regimens and cardiovascular involvement during physical activity.
We included eight multi-center studies with larger sample sizes in our narrative review. The vast majority had an observational and prospective design and included a significant number of athletes [32,33,35,36,39,40]. Furthermore, most multi-center registries reported a mid-to long-term clinical follow-up (the longest being 376 ± 125 days) [37], showing the absence or low prevalence of cardiac adverse events in athletes recovering from COVID-19. However, there is a need for prolonged observation and follow-up of COVD-19-positive athletic populations.

Practical Implications and Need for Future Research
Evidence from the available literature, both single-and multi-center observational studies, suggests low percentages of CV involvement and sequelae after SARS-CoV-2 infection among athletic populations, also at more extended follow-up periods. RTP protocols guide the management of professional and non-professional athletes recovering from the infection, but the strategy is still different among countries. Updated protocols have become available based on accumulating evidence and are now mainly based on a symptoms-driven strategy. When evaluating an athlete or individual practicing sports after a SARS-CoV-2 infection, particular attention should be paid to the course of the infection and its severity. After, the presence of CV symptoms, such as chest pain and palpitations, both during the infection and when returning to exercise, need to be considered a red flag for CV involvement and should suggest the need for further investigation with an ECG, laboratory testing, imaging (TTE and even CMR, if necessary), and exercise testing. However, it must be considered that it is still unclear which approach is best for postinfection athletes' evaluation. Different countries apply different protocols, and trials that compare evaluation approaches have not been conducted but would be beneficial.

Conclusions
Although initial studies reported alarming percentages of SARS-CoV-2 CV involvement, mainly myocarditis, in young athletes' cohorts with a benign course, subsequent evidence from large registries disconfirmed it. On the contrary, most studies showed low CV involvement after COVID-19 among young and healthy athletes. At the same time, studies with more extended follow-up periods in athletic populations became available, reporting fewer adverse cardiac events that were not always linked to the previous infection. Even if encouraging observations emerge from the literature, longer follow-up and systematic evaluation are needed to definitively confirm these findings.

Conflicts of Interest:
The authors declare no conflict of interest.